We have recently completed both a meta-analysis of genome-wide association scans in multiple sclerosis (MS) and a replication effort that validated several novel susceptibility loci, including TNFRSF1A (rs1800693, P=1.6x10-11) which codes for one of the two principal receptors for TNF1. This result is intriguing in the context of reports of exacerbation of central nervous system inflammation in MS patients following treatment with an anti-TNF1 monoclonal antibody. In addition, while this is the first common variant of TNFRSF1A to be definitively associated with an inflammatory disease, many different rare variants are associated with the rheumatologic disease called TNFRSF1A associated periodic syndrome (TRAPS). Our preliminary results suggest that the rs1800693 susceptibility allele causes TNFRSF1A exon 6 to be spliced, producing a transmembrane receptor that lacks the cleavage site necessary to release the soluble form of TNFRSF1A. Our hypothesis is thus that the rs1800693 variant increases susceptibility to MS by decreasing the proportion of soluble TNFRSF1A that is produced, which effectively increases the level of TNF1 activity and could exacerbate inflammatory responses. Since the role of rare variants is not known in MS, we will first explore whether additional, rare TNFRSF1A alleles influence MS susceptibility. With this comprehensive genetic assessment of the locus in hand, we will then explore the functional consequences of rs1800693 and other variants on TNFRSF1A splicing and the formation of soluble TNFRSF1A to test our hypothesis that the level of soluble TNFRSF1A mediates the genetic effect of rs1800693 on MS susceptibility. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to understand the consequences of genetic variation in the TNFRSF1A gene on the function of the human immune system. A variant in this gene increases an individual's risk for developing multiple sclerosis. Thus, understanding how it affects human immune function will allow investigators to better understand the onset of multiple sclerosis, to develop new treatments to prevent onset of multiple sclerosis, and to develop clinical tests that may be able to predict who is at risk of developing multiple sclerosis.